Hagen, N.A., Cantin, L., Constant, J., Haller, T., Blaise, G., Ong-Lam, M., . . . Lapointe, B. (2017). Tetrodotoxin for moderate to severe cancer-related pain: A multicentre, randomized, double-blind, placebo-controlled, parallel-design trial. Pain Research and Management, 2017, 7212713.

To compare the efficacy of tetrodotoxin (TTX) to placebo in patients with pain secondary to advanced cancer or treatment related to treatment of advanced cancer.

Patients with moderate to severe cancer pain for at least two weeks or longer were randomized to receive a dose of TTX 30 µg or placebo twice daily at least six hours apart for four consecutive days. Participants were then seen on days 5, 8, and 15 in clinic for safety and efficacy evaluations and then on a weekly basis for evaluation by phone or in clinic until pain returned to baseline level.

• N = 165 (intent to treat, N = 149)
• AGE: 25-84 years
• MALES: 43%  
• FEMALES: 57%
• CURRENT TREATMENT: Not applicable, other
• KEY DISEASE CHARACTERISTICS: Any diagnosis of cancer; wide range of solid and other tumors
• OTHER KEY SAMPLE CHARACTERISTICS: Aged 18 years or older, stable baseline pain score greater or equal to 4/10 (worst pain in past 24 hours based on BPI, no greater than a three-point differed between highest and lowest scores, and no greater than 50% change in opioid analgesic use without addition of new analgesic), and all had a history or analgesics and maintained the regimens of opioids and co-analgesics. Exclusions: Clinically relevant hypoxia or history of CO₂ retention, severe renal impairment, prolonged QTc, plan for initiation of a new anticancer therapy, and female with positive pregnancy test.

• SITE: Multi-site   
• SETTING TYPE: Multiple settings    
• LOCATION: Full-service hospital or private clinic in Canada, Australia, or New Zealand

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Elder care, palliative care

Multi-center, randomized, double-blind, placebo-controlled, parallel-design trial

Brief Pain Inventory form completed, patient diary

Clinical benefit of TTX over placebo with estimate effect size of 16.2% (p = 0.046) after adjustment with Holm method, p value was nominally significant for two primary endpoints but not at the prespecified two-side 5% level.  Average analgesic response was 57.6 days with TTX compared to placebo at 9.9 days; however, when pain was combined with QOL, there was not a statistically significant difference between those treated with TTX and those with placebo.

TTX administration provides a potential option for uncontrolled moderate to severe cancer pain in patients with advanced cancer that is a non-opioid. TTX provides a different approach to pain via the mechanism of action. However, this drug does not come without side effects/potential adverse effects and, while clinical significance has been demonstrated, this is a modest benefit. The pain reduction was only nominally statistically significant and because of statistical penalties for multiplicity, the study is not considered statistically positive. Therefore, additional study is needed to determine the usefulness of TTX for clinical practice, particularly in those who require high doses of opioids to manage their pain.

Other limitations/explanation: Conflict of interest: funded by Wex Pharmaceuticals; several doctors received operational funding, Dr. Hagen received honorarium, and some of the authors are employees or consultants for Wex Pharmaceuticals. Patients could be on existing pain regimens, unsure if fixed dosing or not

Patients would have to receive via subcutaneous injection. In the study, there were no fatalities and seemed to have a favorable benefit/risk profile. Non-opioid option, although mishandling could cause devastating consequences (TTX can cause paralysis and be fatal in high doses). Patients on high doses of opioids are poor candidates for TTX.